Abstract
Hematopoietic stem cells (HSCs) are defined by their self-renewal, multipotency, and bone marrow (BM) engraftment abilities. How HSCs emerge during embryonic development remains unclear, but are thought to arise from hemogenic endothelium through an intermediate precursor called “pre-HSCs.” Pre-HSCs have self-renewal and multipotent activity, but lack BM engraftability. They can be identified functionally by transplantation into neonatal recipients, or by in vitro co-culture with cytokines and stroma followed by transplantation into adult recipients. While pre-HSCs express markers such as Kit and CD144, a precise surface marker identity for pre-HSCs has remained elusive due to the fluctuating expression of common HSC markers during embryonic development. We have previously determined that the lack of CD11a expression distinguishes HSCs in adults as well as multipotent progenitors in the embryo. Here, we use a neonatal transplantation assay to identify pre-HSC populations in the mouse embryo. We establish CD11a as a critical marker for the identification and enrichment of pre-HSCs in day 10.5 and 11.5 mouse embryos. Our proposed pre-HSC population, termed “11a- eKLS” (CD11a- Ter119- CD43+ Kit+ Sca1+ CD144+), contains all in vivo long-term engrafting embryonic progenitors. This population also displays a cell-cycle status expected of embryonic HSC precursors. Furthermore, we identify the neonatal liver as the likely source of signals that can mature pre-HSCs into BM-engraftable HSCs.
Highlights
Hematopoietic stem cells (HSCs) in adults are the multipotent and self-renewable source of the entire blood system, and hold the regenerative capacity to engraft a myeloablated recipient upon transplantation (Hagedorn et al, 2014)
CD43+ Ter119- Kit+ cells were separated into Sca1+ and Sca1- fractions and co-transplanted into neonatal NSG recipients (Figure 3A). 12 weeks after transplantation, we found that only the Sca1+ fraction consistently produced donor chimerism in the recipient mice, including in secondary recipients, indicating that few, if any, pre-HSCs are contained in the Sca1- population in e11.5 tissues (Figure 3B)
The precise surface marker identity of pre-HSCs in the embryo has remained elusive, hampering efforts to understand how HSCs arise during embryonic development
Summary
Hematopoietic stem cells (HSCs) in adults are the multipotent and self-renewable source of the entire blood system, and hold the regenerative capacity to engraft a myeloablated recipient upon transplantation (Hagedorn et al, 2014). During early embryonic development and prior to the appearance of fully-functional HSCs, distinct waves of blood-forming cells emerge, likely initiated from specialized endothelial cells called “hemogenic endothelium” (Zovein et al, 2008; Lancrin et al, 2009). These waves overlap, with each wave functionally more mature than the last. At e9.5, the first self-renewable and multipotent progenitors, that immediately precede HSCs, emerge in the YS, aorta-gonad-mesonephros (AGM), and PL, and are often called “pre-HSCs” (Yoder et al, 1997a; Taoudi et al, 2008; Arora et al, 2014; Inlay et al, 2014; Rybtsov et al, 2016; Zhou et al, 2016). The FL remains the major site of hematopoiesis until perinatal seeding of the BM (Muller et al, 1994; Beaudin et al, 2016)
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